真核转译起始因子eIF4B在Abl诱导细胞癌变中的作用及其机制

项目名称： 真核转译起始因子eIF4B在Abl诱导细胞癌变中的作用及其机制

项目编号： No.81472611

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈吉龙

作者单位： 中国科学院微生物研究所

项目金额： 72万元

中文摘要： 真核转译异常与肿瘤发生发展密切相关，但其分子机制不详。我们在前期研究中发现, 真核转译起始因子eIF4B参与了Abl癌基因介导的细胞转化过程。在此基础上，本项目将重点探讨eIF4B在携带v-Abl癌基因的鼠白血病病毒恶性转化淋巴细胞过程中，以及在人类Bcr-Abl癌基因诱发细胞癌变和慢性粒细胞性白血病（CML）发生过程中的作用;深入研究Abl转化的细胞中eIF4B调控的下游分子，阐明eIF4B如何在Abl诱导细胞癌变过程中发挥作用；进一步探讨Abl诱导细胞癌变过程中调控eIF4B活性的上游激酶与信号通路，从而揭示Abl癌蛋白通过怎样的机制来调控eIF4B的活性。本项目将应用Abl阳性细胞系、eIF4B敲低转基因小鼠、eIF4B条件敲除小鼠为模型，旨在分子、细胞、动物个体水平上阐明eIF4B在Abl介导细胞转化过程中的作用及其机制。本研究目标不仅旨在理论创新，也为发现药物新靶点提供科学依据。

中文关键词： C25_其它肿瘤；Abl癌基因；真核转译起始因子4B；细胞凋亡；信号通路

英文摘要： Alterations in eukaryotic translation are associated with tumorigenesis but the precise pathogenic processes and mechanistic underpinnings are not well defined. In previous study, we found that eukaryotic translation initiation factor 4B (eIF4B) is involved in cellular transformation induced by Abl oncogenes. Based on this finding, in this project we will focus on the studies of the role eIF4B plays in lymphocytic transformation mediated by v-Abl oncogene of Abelson murine leukemia virus (A-MuLV) and in cellular transformation and development of chronic myelogenous leukemia (CML) induced by Bcr-Abl oncogene. We will identify the downstream targets that are regulated by eIF4B, and determine how eIF4B functions in Abl-induced hematopoietic malignancies. Furthermore, we will identify the upstream kinases and their signaling pathways that are involved in control of eIF4B activity in Abl-transformed cells. These investigations will provide insights into mechanism underlying the regulation of eIF4B function by Abl oncoproteins. In this project, we will use a combination of specific stable cell lines expressing Abl proteins, eIF4B knockdown transgenic mice, and eIF4B conditional knockout mice to address this relationship. Taken together, these experiments using in vitro and in vivo models will provide a very important and novel contribution to our understanding of role and its mechanism for eIF4B during Abl-mediated tumorigenesis, and may highlight eIF4B as a candidate therapeutic target for treatment of Abl-induced hematopoietic malignancies.

英文关键词： other tumors;Abl oncogene;eIF4B;apoptosis;signaling pathways